Form for Submission of Comments s5

15 June 2015

Submission of comments on 'Risk minimisation strategy for high strength and fixed combination insulin products, addendum to the good practice guide on risk minimisation an prevention of medication errors’ - EMA/686009/2014

Comments from: EFPIA

Name of organisation or individual

Sini Eskola ([email protected])

Please note that these comments and the identity of the sender will be published unless a specific justified objection is received.

When completed, this form should be sent to the European Medicines Agency electronically, in Word format (not PDF).

7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7418 8416 E-mail [email protected] Website www.ema.europa.eu An agency of the European Union 1. General comments

Stakeholder number General comment (if any) Outcome (if applicable)

(To be completed by (To be completed by the Agency) the Agency)

EFPIA welcomes the initiative of the draft risk minimization strategy for high strength and fixed combination insulin products with the aim to pro-actively address the risk of medical errors. The risk of medication errors does not exist only with high strengths insulins although it is more important since the approval of these insulins. The risk minimization activities described in this document might be applicable to any strength of insulins. The document is written with a focus on pre-filled injector devices and high strength. EFPIA believes flexibility is needed as devices are developed to meet the needs of different patient populations. It is proposed that the guidance could be reworded to emphasise the need for error-proofing and differentiation to prevent dosing errors rather than mandate that development be limited to a single type of device and to high strength. It is important that the individual Member States should not decide additional need for risk minimisation – This would not be in accordance with the principles behind the European Medicines Agency and the Pharmacovigilance Risk Assessment Committee Since the guide refers also to devices, it would be highly recommended to made reference to some ISO guide (e.g. ISO EN14971; EN IEC62366). Suggestion to add a list of abbreviations as there is a numerous of abbreviations.

2/15 2. Specific comments on text

Line number(s) of Stakeholder number Comment and rationale; proposed changes Outcome the relevant text (To be completed by (If changes to the wording are suggested, they should (To be completed by the Agency) (e.g. Lines 20- the Agency) be highlighted using 'track changes') 23)

Lines 50-52 Comment: Here it is mentioned that the need for risk minimisation could vary across the different Member States – this should not be the case

Proposed change : One set of risk minimisation across Member States Lines 62-64 Comment: If, Pre-filled pens only are considered as part of Line 101 and 103 assumptions, it should be valuable to specify as from here and 118 why other forms such as vials or cartridges are not considered. Lines 62-64 Comment: We believe that dedicated pump/cartridge Lines 100-104 combinations should also be supported as long as appropriate mechanical or software/hardware guarantees the dedicated combination and simple patient interface (such possibilities might also be applied to reusable pens).

The same notion is reasonable for vials if the transfer system into traditional pump reservoirs can be dedicated to that function and restrict vial use with syringes.

We support continued use of currently available concentrated insulins in vials where there is a dedicated syringe and unique patient population needs (e.g. insulin resistance)

Environmental concerns might favour vials over prefilled pens in special circumstances.

We do not support future concentrated insulins in vials unless there is a dedicated syringe and the following considerations (otherwise, we support the exclusion of concentrated insulin

3/15 Line number(s) of Stakeholder number Comment and rationale; proposed changes Outcome the relevant text (To be completed by (If changes to the wording are suggested, they should (To be completed by the Agency) (e.g. Lines 20- the Agency) be highlighted using 'track changes') 23)

vials): a. Dedicated patient populations (e.g. U500) with specific issues like insulin resistance b. Existing patients that fully understand how to dose with concentrated insulins and have done so for quite some time c. For some users, significant or prohibitive cost differences between vial and prefilled pens or pumps d. Environmental objections to prefilled pens given that empty prefilled pens (absent needle) are typically discarded in commercial/home waste, which is consistent with most government regulations addressing disposal of empty pens

Proposed change : “The high strength insulin or the fixed combination insulin product is manufactured in prefilled pens only unless there is a special circumstance.” Line 70 Comment: If bioequivalence is not achieved but therapeutic equivalence is, then additional risk minimisation is not needed. Proposed change: 'If bioequivalence cannot be achieved and the product cannot be judged therapeutically equivalent, the applicant should consider additional risk minimisation measures in line with the provisions in chapter 5.' Lines 72-75 Comment: EFPIA agrees that the pen should reflect the number of insulin units to be administered. Many prefilled insulin pens have an audible and tactile click when the user is dialling the dose; however, the labels warn patients not to set their dose by counting clicks e.g insulin product Tresiba® has one concentration which delivers 2 units of insulin per click.

EFPIA believes users may have the option to adjust dialling doses with different audible and tactile clicks for different products. (For instance, Humulin R U-500 pen delivers 5 units of insulin per click and our Humalog Half-Unit pen delivers 0.5 unit of insulin per click). The dial should always display the dose that is being set and ultimately delivered to the patient.

Our recommendation is, the dose display must reflect the insulin units. For fixed combinations of insulin and another injectable blood glucose-lowering agent the draft guidance must ensure a definition of what is meant by a ‘dose step’ as it also appears in Table 5 (line 171), which states that manufacturers should provide an ‘Explanation of one dose step of .

EFPIA does not agree that every prefilled pen should follow the rule of 1 dose step = 1 click = 1 unit of insulin. (refer to comment on line 111-113).

Proposed change: For products where insulin is combined with another injectable blood glucose-lowering agent in a prefilled pen, the number of ‘dose steps’ is always equivalent to the number of units of insulin to be administered, i.e. the dose counter window on the pen will display the number of dose steps and this will be the same as the number of units of insulin. Line 90 – Section Comment: The addendum should differentiate between 2 higher concentrations and different strengths of specific formulations. Some insulin products are available in more than one strength or concentration and this should not be changed Lines 94-96 Comment: It seems unusual to have to justify why applicable all medication errors listed in Table 1 are not listed in the PV table for safety concerns.

Proposed change: Marketing authorisation holders or applicants should consider provide a justification for any of the potential medication errors listed in table 1 not being addressed as a safety concern in the EU Risk Management Plan in the development of routine and non-routine risk minimisation measures. Line 97 – Table 1 Comment :– All These examples of potential medication error Line 142- Table 2 are not specific for high strength insulins – e.g. 6 th medication Line 153 – Table 3 error - Needle blockage due to non-compliance with the instructions for use is not a medication error or in any way related to strength of the product but rather to ‘product use issue’ according to MedDRA.

Proposed change (if any): To distinguish in the table the medication errors specific to high-dose or fixed-combination if any and others which are common to all insulins. Line 97 – Table 1 Comment: List the same potential medication error category Line 142- Table 2 in each table. Table 1: Medication error due to non-compliance Line 153 – Table 3 with instructions to use a new needle for each injection: this can lead to blockage of needle and subsequent injection of wrong dose, differs from Table 2, Table 3 Medication error due to non-compliance with instructions to use a new needle for each injection: wrong dose injected due to blocked needle Proposed change: Adjusted Table 1 with: Medication error due to non-compliance with instructions to use a new needle for each injection: wrong dose injected due to blocked needle Line 97 – Table 1 Comment: Needle blockage due to non-compliance with the Line 153 – Table 3 instructions for use is not a medication error or in any way Line 170 – Table 4 related to strength of the product but rather to ‘product use issue’ according to MedDRA.

Line 97 – Table 1 Comment: Eight medication error listed “other safety concerns related to medication errors as applicable” would be more comprehensive if completed by examples. Line 97 – Table 1, Comment: Item 4 Fourthmedication error Even if the change from high concentration to low dose concentration doesn’t have the risk of hypoglycemia, there is the risk of loss of glucose control if the patient is under dosed with insulin (specifically in T1DM). Suggestion to add “vice versa”. Proposed change (if any): Medication error associated with switching patients between standard 100 units/ml and higher units/ml strength insulin products and vice versa. Lines 99 - 121 Comment: For some insulin formulation higher concentration make it possible to give higher number of units in one injection which is regards positive for patients with a high insulin need. Also it is expected that future product will be for once weekly administration or even be with longer intervals between injections Different pen systems have different dose and dose increments. Normally from ½ to 2 units. This serves different need from different patient pools and is important in for daily clinical use. By correct use of the pen the patient will get the correct dose. It is important that patients do not count clicks but use the dose counter window which displays the dose in units irrespectively of the strength. Other measures based upon a risk management process compliant with ISO EN 14971 are likely to be effective. Line 101 Comment: No need for the ‘multiple-dose’. There could be future high insulin strength in single use pre-filled devices.

Proposed change: delete ‘multiple-dose Lines 103-104 Comment: If the containers in-use time is shorter than the total usage of the pen the insulin injector device should not be discarded Proposed change: “The insulin injector device should be discarded when the insulin container is empty, unless if the containers in-use time is shorter than the total usage of the pen.” Line 106 Comment: ‘enable repeated dispensing of fixed doses’ indicates that fixed dose rather than flexible dosing is mandated. Proposed change: …‘may enable repeated dispensing of fixed and flexible doses’…

Line 110 Comment: Pens are used by a multitude of patients, from small children who require small doses to very large adults who may require high doses of concentrated insulins. It is not practical to set a specific maximum for a pen to prevent overdose given the variety of patients who will use insulin pens. This text should rather focus on the manufacturer’s responsibility to, through a proper risk management process, compliant with ISO EN14971 to ensure a low and acceptable risk of overdose. Proposed change: The maximum insulin dose per injection should be limited to avoid serious overdose. “Insulin products are designed to fulfil the therapeutic needs of different patient populations. Efforts should be made to establish robust differentiation to avoid accidental overdose.” Line 111-112 Comment: There are marketed products with pre-filled pens with the same active substance where the suggested text does not fit; these products are used by many patients. Propose change: If this is not met - include a sentence in the SmPC to describe this in section 4.2 and in the PIL section

3 Lines 111-113 Comment: We do not agree that ‘dose steps’ should be the Lines 116 - 117 same for all strengths. We agree that the dose counter window should display units of insulin. We do not support the limitation of restricting pen function to 1 unit of insulin for each click of the dose dial. This is problematic for a number of reasons: 1. Restricts innovation by only allowing prefilled pens to last longer a. May increase insulin waste as a function of in-use dating. b. Reduced dose accuracy at lower doses due to increased number of units for same volumetric accuracy (depending upon concentration: U200, U300, and U500) 2. Excludes a more beneficial use of concentrated insulin; facilitating larger max dose settings by increasing dose dial increments (e.g. dialling 2 or 5 units per click): a. For basal insulins where larger doses are common, may decrease number of injections for total dose. b. Helps reduce injection stroke distance for larger doses, which can be limited by hand size and thumb reach.

Both approaches to concentrated insulins have merit (i.e. pens that last longer and pens that offer larger maximum doses). To not allow both approaches favours convenience of changing pens less frequently to what some might argue is the more important objective; allowing for larger max doses and fewer injections to obtain a desired dose. This is particularly important for basal insulins.

In addition devices that administer half units may be necessary and should not be precluded. Proposed change

For pre-filled pens where the same active substance is available in different strengths, the dose steps should be the same for all strengths, ie one dose step corresponds to one unit of insulin at 100units/ml, 200units/ml, 300units/ml etc To ensure consistency with existing insulin products, one dose step of a fixed combination insulin prefilled pen should contain one unit of insulin. Lines 135-138 Comment: The guidance states that applicants are encouraged to consider new invented names. We believe that the ability to have 2 strengths for one brand name must be maintained with the appropriate risk minimisation activities in place. Line 143 – Table 2 Comment: It is recommended to be clear on the difference between mix-up and handling errors in line with how it is normally done when preparing mitigations and utility testing’s Line 143 Table 2 Comment: In order to highlight the warnings in a prominent way, the warnings to be highlighted should be kept to the critical ones e.g. non extraction of insulin from pen to pump. Too many warnings will dilute the effect.

First/Second medication error listed – Design features and use of colour - Recommendation on pack design –  The proposal is not in accordance with the IDF (International Diabetes Federation) colour code which defines the insulin (human insulin) but not the strength http://www.aarogya.com/support- groups/diabetes/insulin-colour-code.html The number of colours available is limited. If two long acting insulins have to choose a colour to differentiate between the short acting insulin and the other strength insulin this doubles the challenge.

It should not be necessary to write units in full. If the

strength is displayed in a way that the units/ml or U/ml is separated and in a different font/colour. Including units in the multi-language pack reduces the available space to display the more critical information of the strength. Line 143 – Table 2 Comment: First/Second medication error – Device recommendations on pack design Whole colour used for the prefilled pen should not be suggested, because strength of colour as a risk control measure, depends on the context of e.g. the pens form, its user interface, other graphical elements, and the differentiation strength of all those elements against the corresponding elements of other pens. A full body colour may be very effective avoiding a mix up with another strength of insulin, but weak in avoiding a mix up of long acting and fast acting insulin. Therefore the text should suggest to rely on a usability engineering process compliant with EN IEC62366 to produce and validate truly differentiating designs, and a risk management process compliant with EN ISO14971 to choose the design that will be related to the lowest overall residual risk. This allows balancing the different mix up scenarios against each other.

EFPIA fail to see that avoidance of extraction from the prefilled pen represents a so severe risk that it needs to be placed on the outer packaging.

When shifting from U100 to a higher strength and bioequivalence between the different strengths is not demonstrated, then it could be considered to provide guidance on the outer packaging. Line 143 – Table 2 Comment:

First/Second medication error listed – Device Recommendation on pack design EFPIA do not support avoiding the use of the same colour in light or dark shades. Since this help the patient identifying the actual drug class e.g yellow and orange indicate a rapid acting insulin Proposed change: Delete example Lines 146 -148 Comment: If the medication errors have been designed out or minimised by packaging etc then it is not necessary to have all the safety messages outlined in Table 3 in the SmPC/PIL. This may lead to confusion. Line 152 Table 3 Comment: 1 st medication error – This warning assumes that the patient is using long and short acting insulins. This warning should be less specific and just recommend checking for the correct insulin. Proposed change:  Warning of medication errors where short acting insulins have been accidently mixed up with long acting insulins  Need to always check the label of the insulin pen before each injection to avoid accidental mix-ups between long acting and short acting insulins Fifth medication error related to extraction misuse – It is proposed that ‘syringe withdrawal’ labelling is ALSO directly on the cartridge holder or pen body as patients discard or loose secondary packaging and PIL/IFU. Proposed change: Labelling outer carton and cartridge holder/pen body section 7 and label section 6

Line 152 – Table 3 Comment: Seventh medication error Insertion of qualitative and quantitative composition in SmPC section 2 is not really helpful as long as the strength is given in section 1 and should therefore be avoided. Proposed change: SmPC section 2 and PIL section 6 • Qualitative and quantitative composition per ml solution of product. Line 152 – Table 3 Comment: It is not clear how the risk is minimised by highlighting the product strength on the packaging, as this to a degree creates the need to also explain "carefully" that the user should not recalculate the dose. The confusion for the user may, given the weakness of information for safety as a risk control measure, actually create a greater residual risk. Lines 153 – 162 Comment: It is useful to remind the reader of the requirements for user testing. There is a lack of reference to the harmonized standard for usability engineering, EN IEC62366 that in conjunction with the harmonized standard EN ISO14971 Risk Management, through proper application, will ensure acceptable risk, regarding all the risks listed in Table 1. Proposed change: … should comply with Articles 59(3), 61(1) and 63(2) of Directive 2001/83/EC and should be consistent with EN IEC62366 and EN ISO14971. Lines 163-164 Comment: Safety messaging to HCPs in addition to labelling should not default to routine risk minimisation – messaging for low risk medication errors will dilute the higher risk medication error messaging. Proposed change: Safety messaging to HCPs should be driven by data from user testing studies and considered

additional risk minimisation measures Line 170 - Table 4 Comments: If there is bioequivalence between different strengths we do not agree that adjustment of doses and timing of concomitant insulins/other medications is needed after switching to a higher strength – it appear contradictory to the clinical situation where no dose-recalculation is needed because the amount of insulin units is the same, only the injected volume is different. Propose change: In the column on key safety messages for HCPs and patients how to avoid mix-ups between different products and different strengths, please add that patients who are blind or with poor vision must be instructed to always get assistance from another person who has good vision and is trained in using the insulin device. Line 171- Table 5 Comment: Statement does not take into account that also a combination drug may be prescribed with a flexible dosing (i.e. adaptation of dose steps). Thus the statement should be removed as anyway ”the number of ‘dose steps’ is always equivalent to the number of units of insulin to be administered“. Proposed change: “Prescribers should state the number of dose steps to be injected, and the dose frequency, on the prescription;” Line 172 - Section This section is flexible and allows deviations from some of the 5 four basic assumptions a-d, requiring additional safety messages, but information for safety may sometimes have a low level of effectiveness compared with other risk control measures such as those implemented by design or protective measures. We suggest to mentioning these since they in practice are available for the manufacturer, through the ISO EN14971 risk management process. Line 191 Proposed change: ‘Should’ should be changed to ‘could’ Line 217-219 Comment:

“Marketing authorisation holders should follow the guidance provided in GVP Module XVI on risk minimisation measures: selection of tools and effectiveness indicators (Rev 1) for effectiveness measures to be included in the EU Risk Management Plan.” Proposed change: Marketing authorisation holders should follow the guidance provided in GVP Module XVI on risk minimisation measures: selection of tools and effectiveness indicators (Rev 1) for effectiveness measures to be included in the EU Risk Management Plan subject to feasibility. Please add more rows if needed.